Exam 4 Flashcards
Empagliflozin non-diabetes FDA indications
Reduce risk of CV death (EMPA-REG trial)
Canagliflozin non-diabetes FDA indications
Reduce risk of MACE
Reduce risk of end-stage kidney disease, doubling of SCr, CV death, hospitalization for HF in patients with T2DM with neuropathy and albuminuria
CANVAS trial
Dapagliflozin non-diabetes FDA indications
Reduce risk of HF hospitalization in patients with T2DM and CVD or multiple CVD risk factors
Tx of heart failure with reduced ejection fraction in adults w/ or w/o T2DM
DECLARE-TIMI 58
Non-diabetes FDA indications for liraglutide, dulaglutide, and semaglutide
Reduce risk of MACE
Sulfonylurea MOA
sulfonylureas bind to the SUR1 receptor on pancreatic beta cells without the presence of glucose or ATP. This closes the ATP-dependent calcium channel opens the calcium channel and triggers insulin release
Sulfonylurea insulin effect
Mixed effect on FPB and PPG
Glipizide Class: Brand: Dose: Duration of action: Active metabolites?
Class: Sulfonylurea Brand: Glucotrol Dose: 5-40mg QD-BID Duration of action: Up to 20 hours Active metabolites? No
Glipizide ER Class: Brand: Dose: Duration of action: Active metabolites?
Class: Sulfonylurea Brand: Glucotrol XL Dose:5-20mg QD Duration of action: 24 hours Active metabolites? No
Glimepiride Class: Brand: Dose: Duration of action: Active metabolites?
Class: Sulfonylurea Brand: Amaryl Dose: 1-8mg QD Duration of action: 24 hours Active metabolites? No
Why are most sulfonylureas QD?
Because most of them have a 24 hour onset of action
Sometimes dosed BID because this decreases the peak effect which decreases the risk of hypoglycemia
Sulfonylureas AE
Hypoglycemia Weight Gain (sulfonylureas promote the release of insulin which is an anabolic hormone and it builds up fat and protein and allows for more glucose to enter the cells)
Less common: rash, photosensitivity, dyspepsia, nausea, HA
Sulfonylureas contraindications
Hypersensitivity
DKA
Type 1 Diabetes
H/O allergic reaction to sulfonamide derivatives (glimepiride)
Concomitant administration of bosentan (glyburide)
Sulfonylureas advantages/disandvantages
Advantages- quick onset, high initial response rate, inexpensive
Disadvantages- hypoglycemia, weight gain, high secondary failure rate (5-10%/year)
Sulfonylureas DDI
CYP2C9
Do you titrate sulfonylureas?
Yes, to minimize the AE if hypoglycemia and to reach target dose
Why is there a high secondary failure rate with sulfonylureas?
Because their activity depends on active, functional beta cells and we lose beta cell mass and function at a rate of 5-10%/year
Meglitinides (Glinides) MOA
Similar MOA to sulfonylurea, the binding site is adjacent.
Difference- requires presence of glucose so hypoglycemia is less common
Meglitinides (Glinides) medications and where they effect BG
Repaglinide, Nateglinide- both rarely used because they are dosed TID before meals so adherence is poor.
Requires glucose so they effect the PPG
Meglitinides (Glinides) adverse effects and contraindications
AE: hypoglycemia and weight gain
Contraindications: hypersensitivity, DKA, T1DM, Repaglinide with gemfibrozil
Meglitinides (glinides) advantages/disadavantages and metabolism
Advantages- Rapid onset of action, less AE than sulfonylureas, postprandial glucose
Disadvantages- hypoglycemia, weight gain, secondary failure (MOA depends on a functional beta cell), and TID dosing
Metabolism- CYP2C8 (DDI with repaglinide and TMP)
Biguanide (metformin) MOA
Primary effect on the liver, it inhibits gluconeogenesis (production of glucose from noncarbohydrate precursors)
Secondarily causes improvement on peripheral insulin resistance
Metformin dose/brand name
Glucophage or Glucophage XR
Dose titration to decrease the AE of diarrhea until maximum dose of 2,550mg/day.
Titrate by increments of 500mg at biggest meal of the day
Even glucophage XR is split into BID dosing to minimize peak effects and decrease AE
What BG does metformin effect?
FPG because the liver is the primary source of glucose in the fasting state
Metformin AE
Common: N/V/D (Diarrhea most common), these effects are transient and will go away with continued use
Uncommon: macrocytic anemia
Metformin contraindications and BBW
Hypersensitivity
eGFR <30mL/min
Active chronic metabolic acidosis
BBW- lactic acidosis
Metformin warnings/precautions
Starting metformin in patients with a eGFR 30-45mL/min is not recommended
IV contrast-induced nephropathy
Hypoxic states (renal failure, liver failure, HF, pulmonary failure increase lactate)
Severe hepatic/pulmonary disease
Cori cycle
Causes an increase in lactate through backup processes. In anaerobic conditions we could see an increase in lactate, contributing to metformin- induced lactic acidosis
Metformin advantages/disadvantages and DDI
Advantages- no hypoglycemia as monotherapy (it does not increase the release of insulin), weight neutral or loss, high initial response rate, positive lipid effects (decrease LDL, TG and increases HDL), inexpensive
Disadvantages- GI AE (take WF to help)
DDI-cimetidine
Thiazolidinediones MOA
Increases insulin sensitivity
Secondarily decreases hepatic glucose production
PPAR-y agonist
Thiazolidinediones adverse effects
Weight gain (glucose enters cell) Fluid retention (increased incidence with insulin) HF exacerbation Fractures Hepatotoxicity Bladder cancer Macular edema
Pioglitazone
Thiazolidinedione
15-45mg QD titrated to therapeutic response
Delayed onset of action so the maximal effect is seen in 8-12 weeks
Mixed effect, but primarily FPG
Thiazolidinediones contraindications
NYHA Class III and IV HF
Thiazolidinedione advantages and disadvantages
Advantages- No hypoglycemia as monotherapy, favorable lipid effects (increase HDL, decrease TG), can use in renal in sufficiency
Disadvantages- delayed onset of action, several potential AE, recommend LFT monitoring
Thiazolidinedione DDI
Gemfibrozil w/ pioglitazone
Max dose of pioglitazone 15mg/day
alpha-glucosidase inhibitors MOA
Prevents breakdown of complex carbohydrates into glucose, delaying and reducing post-meal carb absorption and post prandial BG rise.
Must take WF since it inhibits the breakdown of complex carbs.
alpha-glucosidase inhibitors meds and glucose effect
acarbose and miglitol
Both dose titrated
Effect on PPG
alpha-glucosidase inhibitors adverse effects
Common (directly related to carbs not be digested)- flatulence, abdominal discomfort, diarrhea
Rare- LFT elevation (acarbose)
alpha-glucosidase inhibitors contraindications and warnings/precautions
Contraindications- hypersensitivity, DKA, cirrhosis, IBD, colonic ulceration, intestinal obstruction
warnings/precautions- SCr >2mg/dL
alpha-glucosidase inhibitors advantages/disadvantages
Advantages- no hypoglycemia as monotherapy, weight neutral
Disadvantages- modest efficacy, poorly tolerated GI AE, slow titration, multiple doses/day so poor adherence
DPP-4 inhibitors MOA
DPP4 inactivates or breaks down the incretin hormones (GLP-1 and GIP-1)
The incretin hormones come from the intestines (L cells) and you see a bigger rise after a meal.
In T2DM, you have a decrease in incretin hormones and DPP-4 inhibitors prevent the breakdown of your bodies own GLP-1
What does GLP-1 do?
Gut- delays gastric emptying
Liver- suppresses glucagon secretion
Pancreas- increases insulin release
1- 1 brain- suppresses appetites, increases satiety
What BG do DPP-4 inhibitors effect?
PPG because they only work in the presence of glucose. DPP-4 inhibitors are only around when GLP-1 is around which is when you’re eating
Sitagliptin Class: Brand: Dose: A1C lowering monotherapy: A1C lowering combo therapy: Renal dosing:
Class: DPP-4 inhibitor Brand: Januvia Dose: 100mgQD A1C lowering monotherapy- 0.6% A1C lowering combo therapy- 0.7% Renal dosing: 50mg QD when CrCl 30-50mL/min 25mg/day when CrCl <30mL/min
Linagliptin Class: Brand: Dose: A1C lowering monotherapy: A1C lowering combo therapy: Renal dosing:
Class: DPP-4 inhibitor Brand: Tradjenta Dose: 5mg QD A1C lowering monotherapy: 0.4% A1C lowering combo therapy: 0.7% Renal dosing: N/A
DPP-4 inhibitors AE and drug interactions
AE- nasopharyngitis (runny nose), URI, HA.
Very well tolerated
DDI- CYP3A4
DPP-4 inhibitors contraindications, warnings and precautions
Contraindications- hypersensitivity
Warnings/Precautions- pancreatitis, HF, arthralgia (goes away if you D/C)
DPP-4 inhibitors advantages/disadvantages
Advantages- No hypoglycemia as monotherapy, weight neutral
Disadvantages- expensive
Bile acid sequestrants MOA and medication
Inhibits bile acid reabsorption leading to a decrease in hepatic glucose production
Colesevelam- tk with food
Bile acid sequestrants AE, contraindications, DDI
AE- constipation
contraindications (all because of constipation)- H/O bowel obstruction, TG >500mg/dL, H/O TG-induced pancreatitis
DDI- separate other drugs by 4 hours
Bile acid sequestrants advantages/disadvantages
Advantages- No hypoglycemia as monotherapy, LDL lowering of 15-18%, may increase metformin tolerability
Disadvantages- Modest A1C lowering, high pill burden, may raise TG
Dopamine agonist (Bromocriptine) MOA, effects which BG
Unknown
Increases EPI/NE to improve insulin sensitivity in the liver
Effect PPG
Dopamine agonists (Bromocriptine) AE and contraindications
AE- GI and CNS (N/V, asthenia, constipation, dizziness, somnolence)
Contraindications- hypersensitivity to ergot derivative, lactation, syncopal migraines
Dopamine agonists (bromocriptine) advantages/ disadvantages/ DDI
Advantages- unique MOA
Disadvantages- modest efficacy, AE, cost
DDI- CYP3A4, protein-binding, drug-disease
SGLT2 inhibitors MOA
In T2DM, you see an upregulation of SGLT2. SGLT2 inhibitors inhibit the reabsorption of glucose and glucose gets eliminated in the urine
SGLT2 effects which BG?
It effects both FPG and PPG and has a low risk of hypoglycemia
Canagliflozin
Brand
Dosing Renal dosing
Brand- Invokana
Dosing- 100-200mg daily (can titrate up from lower dose or start from higher one)
Renal dosing- Not recommended if GFR <45
If GRF 30-45 +UACR >300= 100mg daily
EMPA-REG outcome
Empagliflozin gets approved for reduce the risk of CV events
CANVAS trial
Canagliflozin gets approved for reduce risk of CV events
DECLARE-TIMI 58
Dapagliflozin gets approved to reduce risk of HF hospitalization in patients with T2DM and CVD or multiple CVD risk factors
VERTIS CV
Ertugliflozin has no heart benefits
SGLT2 inhibitors AE
Hypotension (bc of water loss) Hyperkalemia Genital mycotic infections UTI Increased urination Euglycemic DKA (why we shouldnt use in T1) Bone fractures (canagliflozin) AKI Bladder cancer (dapagliflozin) Leg/foot amputations
SGLT2 inhibitors contraindications
Hypersensitivity
Severe renal impairment
ESRD
Dialysis
SGLT-2 inhibitors advantages/disadvantages
Advantages- unique MOA, no hypoglycemia as monotherapy, weight loss, decrease in SBP
Disadvantages- AE, cost
Warning for all SGLT2 inhibitors
Necrotizing fasciitis of the perineum (fourniers gangrene), rare-life threatening bacterial infection
How do SGLT2 inhibitors help with HF?
Normally, the SGLT2 inhibitor causes Na and Glucose to be reabsorbed and K to be wasted in the urine.
With a SGLT2 inhibitor, Na, glucose, and water are all wasted in urine.
Consequently, hyperkalemia is possible bc it is being retained
Euglycemic DKA
When BG is normal but a patient still has DKA
when insulin decreases, lipolysis and glucagon increases, this leads to FFA formation which gets broken down into ketones
Look for N/V and abdominal pain
CREDENCE
Canagliflozin
FDA approval to reduce risk of ESRD, double of SCr, CV death, and hospitalization in HF for pts with T2DM and diabetic nephropathy with albuminuria
DAPA-CKD
Dapagliflozin shown to have positive benefits on CKD progression
DAPA- HF
Dapagliflozin
50% pts with diabetes and 50% w/o
Showed benefit in patients with HF
EMPEROR-reduced
Empagliflozin
statistically significant results in HF and decrease risk of CV death
How do SGLT2 inhibitors regulate tubuloglomerular filtration?
Normally, the SGLT2 channel reabsorbs Na and glucose and the rest of the Na gets sent to macula densa which causes the macula densa to sense Na.
In T2DM, there is a hyperfiltration that causes more glucose to be reabsorbed so there is less Na in the macula densa. This tells the body to filter faster causing a progression of CKD.
SGLT2 inhibitors cause more Na to be sent to the macula densa which regulates tubuloglomerular filtration
Amylin analog MOA, drug, BG effects
MOA- amylin is cosecreted with insulin in the beta cell in normal people
Amylin analogs cause synthetic amylin to be secreted which suppresses high postprandial glucagon secretion, increases satiety, and slows gastric emptying
Drug- Pramlintide -for type 1 and 2 DM (Different doses)
Effects PPG so must be administered with meals (lower dose of meal time insulin
Amylin analog adverse effects, contraindications, and warnings/precautions
Adverse effects- N/V, hypoglycemia with insulin (BBW)
Contraindications- hypersensitivity, gastroparesis, unawareness of hypoglycemia
Warnings/precautions- A1C >9%, patients unwilling to SMBG
Amylin analog advantages/disadvantages
Advantages- weight loss
Disadvantages- additional injections, may reduce rate and absorption of drugs because of delayed gastric emptying, GI AE
GLP-1 receptor agonists MOA
Synthetic analog of GLP-1
GLP-1 decreases gastric emptying, decreases glucose production, causes the pancreas to release insulin, and increases satiety
Glucose dependent
Liraglutide Class Brand Dosing Administration Delivery Storage Renal dosing
Liraglutide Class- GLP-1 receptor agonist Brand- Victoza Dosing- 0.6mg SQ daily, titrate weekly to 1.2mg and 1.8mg if tolerated Administration- independent of meals and time of day Delivery- Pen Storage- Room temp for 30 days Renal dosing- NA
Which GLP1 receptor agonists do you have to renal dose?
Exenatide and Exenatide XR
Not recommended with CrCl <30
Lixisenatide (Adlyxin)
ELIXA trial- neutral effect on CV outcomes
Non-human based GLP1 receptor agonists
Semaglutide (Ozempic)
Titrated with 3 doses, first therapeutic dose at 0.5
GLP1 receptor agonist, administor any time of the day with or without meals
Long carbon fatty acid chain is why it has weekly doses
Oral semaglutide
Only oral GLP1 agonist
Rybelsus
PIONEER 6- neutral effect of CV outcomes
co-formulated with SNAC so that the medication gets attached to one area of the stomach
Have to take 30 minutes before eating, drinking, or taking any other medications. Take with no more than 120mL water
LEADER
Liraglutide decreases risk of major CV events
EXSCEL
Exenatide- no significant CV benefits
REWIND
Reduce risk of major CV events
Dulaglutide
SUSTAIN-6
Semaglutide
Decrease risk of CV events
GLP1 receptor agonists AE, contraindications, BBW
N/V/D (Nausea most common)
Injection site reactions or nodules (bydureon)
Contraindications- hypersensitivity, personal or family history of medullary thyroid carcinoma, patients with MEN 2
BBW- risk of thyroid C-cell tumors
GLP1 receptor agonists advantages and disadvanteges
Advantages- weight loss, convenient dosing
Disadvantages- May reduce rate and absorption of drugs, injections/training, must stay hydrated or prerenal AKI possible
Xultophy
Insulin degludec and liraglutide
QD injection
Dose range 10-50
Soliqua
Insulin glargine and lixisenatide
Administer 1 hr before 1st meal of day
Insulin pharmacology
Insulin is a protein that is made up of AA. It comes from proinsulin.
If you make insulin, you also make C-Peptide.
It is stored in crystals (hexamers around a zinc molecule) and degraded in the liver and kidneys.
Half life of 3-5 minutes
Rapid acting insulin
Insulin lispro (Humalog)
Insulin aspart (Novolog)
Insulin glulisine
(Admelog is similar but not approved to be bioequivalent)
-All insulin analogs , which are predictable! The have the lowest variability of absorption (5%).
Stabilized into hexamers by a cresol preservative. Rapid-acting insulin rapidly goes from hexamer to monomer form for diffusion.
Take about 15-20 minutes before a meal.
Fiasp
Faster acting insulin aspart
Ultra-rapid acting (has a 10 minute earlier onset of action than the rapid acting insulins)
Contains niacinamide (Vit B3 as an excipient that increases the absorption)
Inject at the start of a meal or within 20 minutes after starting a meal. Allows for more variability in timing.
Lyumjev
Faster acting insulin lispro
Comes in 100 and 200 units/ml
Excipients:
citrate- increases vascular permeability
Treprostinil- increases local vasodilation
Both allow for a quicker absorption
Administration- inject at the start of a meal or within 20 minutes after starting a meal
Inhaled insulin
Afrezza (human insulin, ultrarapid acting)
Acts more like a rapid acting analog
Indications- T1DM or T2DM adult, must be used with long-acting insulin if used in T1DM, not recommended for DKA or smokers
Contraindications- chronic lung disease, asthma, COPD
Warnings- decline in pulmonary function, lung cancer
Need to measure FEV1 and respiratory function
BBW- acute bronchospasm in patients with asthma/COPD
Meal time insulin
Afrezza storage
Inhaler- good for 15 days
cartridges- good for 10 days at RT when sealed, 3 days when opened
Afrezza dosing
Use a 1.5x conversion
limited to 4, 8, or 12 units
You need more afrezza than your typical meal time insulin
Injected meal time insulin 5-8 units, afrezza dose 8units
Short-acting insulin
Regular insulin (human)
Self-aggregate in antiparallel fashion to form dimers and then stabilize around zinc ions to create hexamers
When injected it gets diluted by the interstitial fluid and goes from hexamers to dimers to monomers. It undergoes the dimer step to increase the onset of action.
Human insulin so variability in dose and PK/PD profile.
Because of the slower onset of action, must be given 30 minutes prior to a meal.
1st phase release of insulin
Insulin-independent GLUT2 receptor on the beta cell causes the calcium channel to open and insulin to be released.
Insulin is stored in the beta cell (this is messed up in T2DM)
Phase 2 release of insulin
Insulin meets the insulin receptor and undergoes a network of phosphorylation’s that activate the GLUT4 (insulin dependent) receptor. GLUT4 (on muscles and adipose tissues) then accepts glucose into the cell to become metabolized
Where does insulin come from?
Beta cells
Synthetic insulin used to come from beef and pork sources but we dont use this anymore due to impurities
We use recombinant insulin made from bacteria and yeast
Human insulin vs. insulin analogs
Human insulin is any insulin, regardless of if you make it yourself, that has the same AA structure as the insulin we make in our own bodies,
Insulin analogs have AA switches that change the PK/PD effects.
Human insulin examples
Insulin glargine
Regular insulin
NPH
Insulin analogs examples
Insulin lispro
Insulin aspart
Insulin detemir
Insulin glulisine
Humulin R U-500
Typically reserved for patients requiring more than 200units/day of insulin which indicates insulin resistance.
Very dangerous so be extra sure that patient understands and uses correct syringe.
Intermediate-acting insulin
NPH insulin (human insulin) Novolin R or Humulin R Combination of insulin and protamine to increase duration of action. After injection, proteolytic tissue enzymes have to degrade protamine bound to the insulin hexamers before the insulin can be broken down into the dimer and monomer forms.
Insulin is cloudy due to the protein, do not shake but roll in hands
Long-acting insulin
Insulin glargine (Lantus) is soluble in acidic solutions so once it goes into the neutral bodies pH it precipitates into a crystalline depot. Individual insulin molecules slowly break away. Basaglar is also insulin glargine but they are not interchangeable.
Insulin detemir- self-aggregates due to albumin binding. Dose dependent profile (<0.3units/kg= BID, >0.3units/kg=QD)
Insulin degludec- multiple hexamer formation resulting in a SQ depot. It has reversible albumin binding.
Toujeo
Insulin glargine U-300 (concentrated long acting insulin)
Need 10% more Toujeo to meet needs, we dont know why.
1.5mL SoloStar or 3mL Max SoloStar
Indications: glycemic control in diabetes mellitus, not used for DKA
Can cause hyper or hypo glycemia with changes in insulin regimen
Only comes in a prefilled pen
Tresiba
Insulin degludec
U-100 or U-200 FlexTouch
Longest duration of action (42 hours). Builds into multihexamers once injected which causes this long DOA.
Dose daily at any time of the day
Allow for 3-4 days before dose increases
Allow a minimum of 8 hours between consecutive injections
Insulin stacking
Increases risk of hypoglycemia
We are worried about this in the shorter acting insulins
With longer acting insulin we do not worry because they reach steady state in a few days
Premixed insulin
Typically reserved for patients who have cost issues or will not take more than 2 injections per day.
%70/30= 70% NPH (bound to protein)/ 30% regular insulin (not bound)
Give at breakfast and dinner
Which insulin is given IV?
Regular insulin
Which insulins have a duration over 24 hours?
U-300 glargine and degludec
Which insulins have a duration under 5 hours?
Technosphere, glulisine, lispro, aspart
Which insulin has a duration between 4-6 hours?
Regular insulin
Which insulin has a duration between 8-12 hours?
NPH
Which insulins have a duration between 14-24 hours?
Detemir
Glargine (U-100)
Insulin adverse effects
Hypoglycemia is the most common
Weight gain (insulin is anabolic and builds up fat and protein)
Injection site reactions (not as common)
Hypoglycemia
Typically BG <70mg/dL
S/S- Tremor, diaphoresis (sweating), lightheaded, HA, tachycardia, nervous/anxious, irritable, confusion, hunger, drowsiness
Use the Rule of 15 to treat hypoglycemia- consume 15g of simple carbohydrates (orange juice, glucose tablets) and retest in 15 minutes. Retest until BG is normalized.
Hypoglycemic unawareness
Loss of warning signs and S/S of hypoglycemia
What are the 5 counterregulatory hormones and what do they do?
They increase BG
Glucagon, Epi, NE, Cortisol. GH
When do you start seeing severe symptoms of hypoglycemia?
BG under 40
Hypoglycemia level 1
Glucose 54-70mg/dL
Hypoglycemia Level 2
Glucose <54mg/dL
Hypoglycemia Level 3
A severe event characterized by altered mental and/or physical status requiring assistance.
Glucagon
For adults and children over 6 years old-
1mg (1mL) IM repeat in 15 minutes if needed
For children <6
-0.5mg (0.5mL) IM repeat in 15 minutes if needed
Place patient on side in position to avoid aspiration from vomit and call 911.
Gvoke and GvokeHypoPen
SQ preconstituted glucagon administration
For ages >2
Works like an epipen
Glucagon nasal powder
For ages 4 and up
Basal insulin
The insulin that your body produces at all times regardless of carb intake
Prandial insulin
The insulin that your body produces after meals
Treatment for T1DM
Patients should be treated with multiple daily injections
Pick either
-Basal and prandial injections
-Continuous subcutaneous insulin infusion
Most patients should be educated in matching prandial insulin dose to carbohydrate intake, premeal blood glucose, and anticipated activity.
Insulin analogs are preferred
Total Daily Dose
For a new diagnosis begin with 0.5units/kg/day.
This will be adjusted for patient-specific needs
Insulin needed for entire day
Basal-bolus dosing
Step 1:
Calculate TDD (insulin needed for entire day)
Step 2:
Split this dose in half. 50% will go to basal dose (NPH or long acting insulin) and 50% will be given before each meal (this 50% is divided by 3 and is given via rapid acting insulin or ultra rapid acting insulin)
Split-mixed dosing
2 injections/day
Calculate TDD and then split into 1/3rds.
2/3rds of TDD will be given in the morning to account for breakfast and lunch
1/3rd given at night to account for dinner. Less given at night to prevent hypoglycemia while sleeping.
Continuous subcutaneous insulin infusion
Uses rapid acting insulin
Mainly aspart (novolog) or lispro (humalog)
Typically given at the patients basal rate (0.5units/kg/hour)
Correction Factor
Also called insulin sensitivity
Calculated to estimate the approximate plasma glucose lowering effect of 1 unit of short-acting insulin.
Example: If you correction factor is 50 then 1 unit of insulin will lower your BG by 50mg/dL
Corrects premeal glucose
How do you calculate correction factor?
Regular insulin- 1500/TDD
Most common** Rapid acting- 1700/TDD
How to calculate meal-time insulin doses
1.) Initial TDD is an estimate, it will be adjusted. Once we understand the patients true TDD we will move on to carb counting.
2.) 50% TDD is basal and 50% is prandial
Divide the 50% prandial insulin into 3 and give at
each meal. Calculate the correction factor for the
patient (1700/TDD) and add insulin based off of the
correction factor. Goal glycemic range is 80-
130mg/dL.
How do you make a correction factor scale?
Goal is 80-130mg/dL
Anything less than 80mg/dL, you subtract 1 unit from the dose.
The CF is then used to make the scale. If the correction factor was 30 then every 30 mg increase in BG you give 1 extra unit of insulin
Carbohydrate counting
Very effective
Use I:CHO ratio
Example- if your I:CHO ratio was 15 then 1 unit of insulin will cover 15 grams of carbs. If you are eating 30 carbs you would give 2 units of insulin.
Calculation:
Rule of 500-
500/TDD= I:CHO ratio for rapid-acting insulin
450:TDD= I:CHO ratio for regular insulin (less common)
Insulin management priority list
Keep BG between 80-130mg/dL
- ) Target lows first
- ) Look at FPG and fix next
- ) Look for a 3-4 day pattern in the glucose log
- ) Identify the insulin dose that is responsible for the increase or decrease in BG
- ) Adjust this dose by 10-20%
Only adjust 1 dose at a time and then look for a new pattern.
Pre-breakfast BG value is caused by what?
Meal- Dinner/bedtime
Insulin-
Basal-bolus- Bedtime (long-acting)
split-mixed- (Pre-dinner NPH)
Pre-lunch BG value is caused by what?
Meal- Breakfast
Insulin-
Basal-bolus and split mixed- pre-breakfast insulin (rapid-acting)
Pre-dinner BG value is caused by what?
Meal-lunch
Basal-bolus- Pre-lunch dose (rapid acting insulin)
Split-mixed- pre-breakfast dose (NPH)
Bedtime BG value is caused by what?
Meal- Dinner
Insulin-
Basal-bolus- Pre-dinner insulin (rapid acting)
Split mixed- (Pre-dinner insulin (rapid acting)
How does physical activity affect insulin?
Causes hyperglycemia due to “fight or flight” response caused by NE or EPI
Causes hypoglycemia due to the overexpression of the GLUT1 (insulin dependent) receptor. This increases the sensitivity of this receptor for 7-11 hours postexercise.
Recommendations to decrease risk of hypoglycemia with exercise
Make sure preexercise BG is >100mg/dL Increase food intake Reduce prandial insulin Reduce overnight basal insulin SMBG PRN Simple carbs
Potential risks of hyperglycemia
Underestimating carb intake High fat meal Missed/inadequate medication doses Ineffective insulin Poor administration technique Overuse of injection site Less than usual activity medications Illness, pain, stress
Potential causes of hypoglycemia
Irregular timing of medications Incorrect medication dosing Overestimation of carb intake Skipping/delaying meals More than usual activity Decreased insulin needs (weight loss, increased physical activity)
Lipohypertrophy
Build up of fat tissues because of insulin administration.
Need to rotate injection sites
Patients with this might need to increase insulin doses due to insulin not being absorbed
Dawn phenomenon
When hormones are released in the mornings because they have different cycles. You need to check overnight insulin to determine if hypoglycemia is in?caused by the dawn phenomenon
Which injection site has the most rapid absorption of insulin?
Abdominal fat
Hybrid closed loop system
Medtronic and T:slim
CGM
insulin pump with tubing
Control-IQ technology
CGM with no tubing
Sick day management
Continue basal insulin at normal dose If not eating: D/C premeal insulin and cover hyperglycemia with rapid-acting insulin Q 4-6 hours Stay hydrated Monitor every 1-2 hours Check ketones every 4 hours if BG>250
Call MD if vomiting and BG >500 or moderate urine ketones
Prediabetes recommendations
Intensive behavioral lifestyle intervention programs
Achieve and maintain 7% loss of initial body weight
Moderate intensity exercise to at least 150min/week
Annual monitoring
Metformin 850mg BID should be used if
BMI>35
Age <60
H/O GDM
Pharmacotherapy for T2DM
Metformin preferred
Consider initiating insulin therapy if newly diagnosed, symptomatic, A1C >10% and/or BG >300mg/dL
Consider initiating dual therapy in newly diagnosed pts if A1C is 1.5-2% above target
In most patients, GLP-1 RA are preferred over insulin
Youth-onset T2DM
3 approved drugs- insulin, metformin, liraglutide
If insulin targets are not met with metformin +/- basal insulin in children over 10 add liraglutide
What do you give to T2DM patients who are on metformin and have ASCVD
GLP-1 RA with proven benefit (Liraglutide, Dulaglutide, Semaglutide)
OR
SGLT-2 inhibitor with CVD benefit (Empagliflozin, Canagliflozin)
If A1C still above target: For patients on GLP-1 RA add SGLT2 inhibitor Add Dpp-4 if not on GLP-RA Basal insulin TZD SU
What do you glve to T2DM patients who are on metformin and have HF or CKD
SGLT2 with evidence if GFR adequate (Dapagliflozin, Canagliflozin, Empagliflozin)
OR
Only if SGLT2 cant be used give GLP1-RA with proven CV benefits (Liraglutide, Dulaglutide, Semaglutide)
If A1C still above target: For patients on SGLT2 inhibitor consider GLP1 RA Add Dpp-4 if not on GLP-RA Basal insulin SU
What do you give T2DM patients if cost is a major issue?
SU or TZD
What do you give T2DM patients who need to lose weight?
GLP1-RA or SGLT2
What do you give in T2DM patients who need to minimize hypoglycemia?
DPP4
GLP1-RA
SGLT2i
TZD
When do you add insulin to a T2DM patient?
If not meeting goals and already on GLP1-RA or GLP1-RA not tolerated add basal insulin
Start at 10IU/day or 0.1-0.2units/kg/day
How do you titrate basal insulin for T2DM?
Start at 10IU/day or 0.1-0.2units/kg/day
10-20% every 2-3 days
What do you do if T2DM patient is on basal insulin and not meeting goals?
Add prandial insulin
One dose with largest meal of day
Initiation- 4U a day or 10% of basal dose
Titrate by 1-2 IU or 10-15% twice weekly
What to do if A1C above target in T2DM patients and patient is on basal and prandial insulin correctly titrated
Stepwise additional injections of prandial insulins and potentially proceed to full basal-bolus insulin
Consider split mixed regimen
Consider twice daily premixed insulin
Critical point for basal insulin T2DM
0.5units/kg or higher we worry about over-basalization of increasing basal doses. So the increasing basal doses are not working as effectively and you might need them
Stress hyperglycemia
Illness can cause hyperglycemia by increasing stress hormones (cortisol and EPI)
Hyperglycemia can lead to organ failure, sepsis, and death
Hyperglycemia in hospitalized patients
Any BG >140mg/dL
BG levels that are consistently above this may require treatment
A1C >6.5% suggests that diabetes preceded hospitalization
Critically ill patients (ICU) with hyperglycemia
IV insulin when BG gets between 140-180mg/dL
Maintain a BG target of 140-180mg/dL
Never let BG get below 110
Insulin infusion protocols are highly recommended
Noncritically ill patients with hyperglycemia in hospital
Maintain BG target of 140-180mg/dL
Scheduled SQ insulin that delivers basal, nutritional, and correction components recommended
Oral antihyperglycemics in the hospital
Limited data
Concerned because of long duration of action of agents, NPO, limited oral intake, and alternative nutrition therapies (TPN)
IV insulin dosing in hospital
Protocols in specific hospitals determine rate
1unit/mL in 0.9% NaCl
Basal-bolus regimen in hospitalized patients
Preferred method in non-ICU patients
- ) Determine the basal dose (Take 2/3rd of the total dose given in the ICU)
- ) Determine TDD (basal dose x2)
- ) Bolus insulin dose. These patients are eating very little so give 10% of basal dose for each meal. This will increase as the patient starts eating more.
- ) Correction scale measurement based off of patients CF.
Hypoglycemia triggers in hospitalized patients
Sudden reduction in corticosteroid dose Altered ability to report symptoms Reduced oral intake Emesis New NPO status Inappropriate timing of insulin Reduced infusion rate of dextrose Unexpected interruption in TPN or parenteral infusions
Hypoglycemia protocol if patient can take PO
BG <70 stop insulin
If BG 50-70 start rule of 15
If <50- give 30 grams carbs
Hypoglycemia protocol is patient cannot take PO
If awake: D5W 25mL IV push
If not awake:D5W 50mL IV push
No IV access- glucagon 1mg IM
Inpatient glucose monitoring
Bedside POC method preferred
If receiving nutrition, check prior to any carbs
If not receiving nutrition check q 4-6 hrs
IV insulin- check every 30minutes- 2 hrs
Enteral nutrition
Tube feed
Parenteral nutrition
Through IV, TPN
Glucocorticoid induced hyperglycemia
Elevated PPG BG
Glucocorticoids increase insulin resistance
Glucocorticoid induced hyperglycemia treatment
Once daily prednisone and insulin naive-
NPH 0.1unit/kg for every 10mg prednisone
Once daily prednisone and at home insulin-
Add weight based total to normal basal insulin dose
Twice daily prednisone or dexamethasone- long acting insulin
Does DKA or HHS have higher mortality?
HHS
Diabetic ketoacidosis
Typically type 1 DM
Uncontrolled hyperglycemia causes increased ketone production which leads to a metabolic acidosis
Hyperosmolar hyperglycemic state
Typically Type 2 DM
Severely high BG, dehydration, and hyperosmolality
Counterregulatory hormones in DKA and HHS
All are increased
DKA- absolute insulin deficiency
HHS- relative insulin deficiency
What is the most common precipitating factor for DKA?
Infection in known T1DM patients
Newly diagnosed T1DM
Why do some women not take their insulin?
Hyperglycemia causes weight loss and insulin causes weight gain
Clinical presentation of DKA
polyuria, polydipsia, weight loss, N/V, abdominal pain, dehydration, weakness, mental status changes, poor skin turgor , Kussmaul respirations, tachycardia, hypotension
Kussmaul respirations
Pt has abnormal respirations because body is trying to blow off CO2
DKA
Diagnostic features of DKA
Elevation in total blood ketone concentration
Ketones in urine- acetoacetate and acetone
Ketones in blood stream- beta-hydroxybutyrate
MUDPILES
Anion-gap metabolic acidosis Methanol toxicity Uremia DKA Paraldehyde toxicity Infection Lactic acidosis Ethylene glycol toxicity Salicylate toxicity
Anion gap metabolic acidosis
Anything >10-12mEq/L
Why do you check amylase and lipase in anion gap metabolic acidosis?
They are raised if the cause is pancreatitis
DKA findings: pH- Sodium bicarb- Urine ketone- Serum ketone- Serum osmolality- Anion gap- Mental status-
pH- <7.3 (more severe with lower pH) Sodium bicarb- <18 (the lower the bicarb is the more severe) Urine ketone-Positive Serum ketone-Positive Serum osmolality- Variable Anion gap- >10-12 Mental status- Alert to coma in severe
HHS findings: pH- Sodium bicarb- Urine ketone- Serum ketone- Serum osmolality- Anion gap- Mental status-
pH- >7. 3 (more normal) Sodium bicarb- Normal (>18) Urine ketone- Small to none Serum ketone- Small to none Serum osmolality- >320mOsm/kg Anion gap- Variable Mental status-Stupor/coma
Treatment goals of DKA and HHS
Correct dehydration, hyperglycemia, and electrolyte imbalances
Treat with fluids, insulin (treating acidosis!), and electrolytes
Fluid therapy for treatment of DKA
Give 1-1.5 L in first hour 0.9% NaCl bolus immediately while waiting on labs.
If corrected Na normal or elevated- 0.45% NaCl at at rate of 250-500mL/hr
If corrected Na low- 0.9% NaCl at a rate of 250-500mL/hr
When do you want to see correction in DKA?
Fluid deficit- w/in 24 hours
Hyperglycemia- w/in 6 hours
Ketoacidosis- w/in 12 hours (this is why you continue giving insulin past when the hyperglycemia is fixed)
DKA dosing insulin therapy
Regular insulin
0.1units/kg bolus followed by a 0.1unit/kg/hour infusion
OR
0.14units/kg/hr infusion
You are not titrating insulin
Goal is to not drop glucose too quickly
When do you reduce rate of insulin therapy in DKA?
When BG is 200mg/dL you reduce rate to 0.02-0.05units/kg/hr and give D5W
Goal BG 150-200mg/dL until resolution of DKA
When do you give K with DKA?
If K <3.3
-Hold insulin and give K 20-30mEq/L until K >3.3
If K 3.3-5.2
-20-30mEq K/L of replacement fluid with insulin
If K > 5.2
Do not add K
Check serum K in 2 hours
When do you give bicarb in DKA?
When pH <6.9 give 100mEq bicarb
Criteria for resolution of DKA
BG <200mg/dL Two of the following: Serum bicarb >15mEq/L Venous pH >7.3 AG <12
Criteria for resolution of HHA
Normal osmolality
Normal mental status
Transition to SQ insulin after DKA
Make sure there is an overlap of 1-2 hours between discontinuation of insulin infusion and administration of SQ insulin
Complications of treating DKA
Hypokalemia
Hypoglycemia (BG monitoring q 1-2h)
Hyperchloremia
Cerebral edema
HHS causes
Typically in older adults due to restricted water intake.
It involves over days to weeks
Energy balance
Energy intake- total energy expenditure
TEE
resting metabolic rate (RMR) x physical activity level (PAL)
Physical activity level
Sedentary- 1.2
Low to moderate- 1.4
Active- 1.6
Carbohydrates
4 calories/gram
45-65% total calories
Simple sugars
Fructose, fruits, milk (lactose)
Less than 10% calories/day added sugars
Complex starches
Beans, peas, nuts, grains, starchy vegetables
Complex fiber
Insoluble- helps maintain a healthy digestive system and regularity
Soluble- Helps control BG and cholesterol
14 grams of fiber for every 1,000 calories
Protein
4 calories/gram
10-35% of total calories
0.8grams /kg/day of protein
Animal sources, plant s (soy, beans, nuts, quinoa
Fat
9 calories/gram\
20-35% of total calories from fat
Monounsaturated fatty acids
Healthy
Avocadoes, nuts, seeds, olive oil, canola oil, peanut oil
Polyunsaturated fatty acids
Healthy
ALA, soy beans, walnuts, flax seeds, DHA/EPA, salmon and other seafood
Trans fatty acids
margarines and processed foods
Unhealthy
Saturated fatty acids
Unhealthy
Animal fat, coconut oil, palm oil, cocoa oil
Less than 10% of calories should come from fats
Daily sodium recommendations
Less than 2300mg/day
Alcohol
7 calories/gram
Up to 2 drinks for men and 1 for women per day
Healthy eating plate
1/2 fruits and veggies
1/4 whole grains
1/4 healthy protein
skip sugary drinks
Starches grams of carbohydrate per serving
15
Fruits grams of carbohydrate per serving
15
Milk grams of carbohydrate per serving
12
Nonstarchy veggies grams of carbohydrate per serving
5
Meat, proteins, and fats grams of carbohydrate per serving
0
Women carb requirements
Need about 45-60 grams carbs at each of 3 meals and 15 grams for snacks prn
Men carb requirements
Need 60-75 grams carbs at each 3 meals and 15-30 grams carbs for snacks prn
Is there an ideal percentage of calories from carbs, proteins, and fat for people at risk for diabetes?
No
ADA total dietary allowance of carbs for adults w/o diabetes
130g/day to fulfill brains requirement
Two systematic reviews of the literature regarding GI and GL in individuals with diabetes report
No A1C impact
Does the ADA support limiting carbs for the general population?
No
Healthcare providers should focus on:
Emphasize nonstarchy veggies
Minimize sugars and refined grains
Choose whole foods over highly processed foods
Reduce carbs in pts with DM
Weight management
In T2DM, 5% weight loss is recommended. Optimal outcomes are seen at 15% or more weight loss if feasible
Diabetes remission
Maintenance of euglycemia or prediabetes level of glycemia with no meds for 1 year
Excess alcohol consumption can lead to
Hyperglycemia
Alcohol in people with DM can inhibit gluconeogenesis and cause hypoglycemia
Etiology of obesity
Imbalance between energy intake and energy expenditure over time
Medications associated with weight gain
Anticonvulsants/mood stabilizers Antidepressants Beta blockers antidiabetics Atypical antipsychotics Antihistamines Corticosteroids Hormonal contraceptives
Leptin
Comes from fat cells and decreases appetite.
There is a leptin resistance in obesity.
What does an increase in FFA cause?
An increase in insulin
-weight gain and insulin resistance
Defining obesity
A state of excess body fat as determined by measures in adiposity
BMI is used but does not take into account fat free mass
Can take intraabdominal fat waist circumference
BMI calculation
Weight in kg/height in m^2
Normal BMI
18.5-24.9 kg/m^2
Obesity BMI
> 30 kg/m^2
Measuring waste circumference
Narrowest circumference in area between last rib and top of iliac crest
High risk
men >40
women >35
Weight loss goals
Initial goal: 5-10% loss of baseline weight w/in 6 months
Create an energy deficit of 500-750kcal/day
Women- 1200-1500 kcal/day
Men- 1500-1800 kcal/day
When would you consider medications in obesity?
BMI >30
BMI> 27 with at least 1 associated obesity related condition
When would you consider metabolic surgery in obesity?
BMI >40
BMI >35 with obesity associated comorbid conditions
When do you D/C medication for obesity?
In pregnancy
If the response is less than 5% after 3 months
Phentermine
Approved for short term use
Controlled substance
MOA- NE releasing agent
Contraindications- anxiety disorders, heart disease, HTN, seizures, MAOI, pregnancy/breast feeding, hyperthyroidism, glaucoma, drug abuse, idiosyncrasy to symathomimetic amines
Orlistat
Chronic use
Alli- OTC
Xencal- Rx
Pancreatic and gastric lipase inhibitor
Contraindications- chronic malabsorption syndrome, cholestasis, oxalate nephrolithiasis, pregnancy/breastfeeding
Phentermine/Topiramate
Dose titration
MOA- GABA receptor modulation plus NE releasing
Chronic
Naltrexone/Bupropion
BBW- suicidal ideation
Goal dose 2 tablets BID 32/360mg
Chronic
Reuptake inhibitor of Ne and dopamine; opioid antagonist
Saxenda
Liraglutide
Chronic
GLP1 RA
Metabolic surgery
Achieves superior glucose control and reduction in CV risk factors in obese patients with T2DM
Metabolic surgery RYGB
Gastric bypass
Most favorable risk-benefit ratio
Metabolic surgery VSG
30% of procedures
Excellent weight loss
Long term studies needed
Metabolic surgery LAGB
19% of procedures
Greater risk of complications
Metabolic surgery BPD-DS
2% of procedures
Most effective but least favorable risk-benefit profle
Consider if BMI >60
